Loss of coxsackie and adenovirus receptor expression in human colorectal cancer: A potential impact on the efficacy of adenovirus-mediated gene therapy in Chinese Han population

Abstract

The coxsackie and adenovirus receptor (CAR) is considered a tumor suppressor and critical factor for the efficacy of therapeutic strategies that employ the adenovirus. However, data on CAR expression levels in colorectal cancer are conflicting and its clinical relevance remains to be elucidated. Immunohistochemistry was performed on tissue microarrays containing 251 pairs of colon cancer and adjacent normal tissue samples from Chinese Han patients to assess the expression levels of CAR. Compared with healthy mucosa, decreased CAR expression (40.6% vs. 95.6%; P<0.001) was observed in colorectal cancer samples. The CAR immunopositivity in tumor tissues was not significantly associated with gender, age, tumor size, differentiation, TNM stage, lymph node metastasis or distant metastasis in patients with colon cancer. However, expression of CAR is present in 83.3% of the tumor tissues from patient with colorectal liver metastasis, which was significantly higher than those without liver metastasis (39.6%; P=0.042). At the plasma membrane, CAR was observed in 29.5% normal mucosa samples, which was significantly higher than in colorectal cancer samples (4.0%; P<0.001). In addition, the survival analysis demonstrated that the expression level of CAR has no association with the prognosis of colorectal cancer. CAR expression was observed to be downregulated in colorectal cancer, and it exerts complex effects during colorectal carcinogenesis, potentially depending on the stage of the cancer development and progression. High CAR expression may promote liver metastasis. With regard to oncolytic therapy, CAR expression analysis should be performed prior to adenoviral oncolytic treatment to stratify Chinese Han patients for treatment.

Figure 1

Immunohistochemical analysis of CAR in colon cancer and normal tissue. (A) Immunostaining of CAR in normal colon tissue, positive staining was observed in the cytoplasm and, predominantly, the membrane. (B) Immunostaining of CAR in poorly differentiated colon cancer, positive staining was predominantly observed in the cytoplasm. (C) Immunostaining of CAR in moderately differentiated colon cancer, positive staining was observed in the membrane and, predominantly, the cytoplasm. (D) Immunostaining of CAR in colon cancer with liver matastasis, positive staining was observed in the cytoplasm and membrane. Magnification, ×400. CAR, coxsackie and adenovirus receptor.

Figure 2

Kaplan-Meier survival curve analysis in patients with positive and negative CAR expression demonstrating CAR expression has no significant association with overall survival. CAR, coxsackie and adenovirus receptor.